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  • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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  • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
  • C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
  • C07C215/26—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing rings other than six-membered aromatic rings
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  • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
  • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
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  • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D263/18—Oxygen atoms
  • C07D263/20—Oxygen atoms attached in position 2
  • C07D263/24—Oxygen atoms attached in position 2 with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms
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  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
  • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
  • C07D277/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
  • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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  • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
  • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
  • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
  • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
  • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

• the present invention relates to amino acid derivatives.
• amino acid derivatives of the general formula wherein R1 is hydrogen or methyl, R2 is ethyl, propyl, isopropyl, imidazol-2-yl, imidazol-4-yl, pyrazol-3-yl, thiazol-4-yl, thien-2-yl or t-butoxy, R3 isobutyl, Cyclohexylmethyl or benzyl, R4 and R5 independently of one another each hydrogen, optionally by amino, monoalkylamino, dialkylamino, alkanoylamino, alkanoylamino, carboxy, alkoxy or hydroxyl, mono- or polysubstituted alkanoyl or an O-protecting group or together a cyclic O-protecting group, R6 one of the groups mean, wherein D is a methine group or a nitrogen atom, R7 alkyl, aryl or aryl
• the present invention relates to the compounds of the formula I and their pharmaceutically usable salts as such and for use as active therapeutic substances, the preparation of these compounds, furthermore medicaments containing them and the preparation of such medicaments, and the use of compounds of the formula I and their pharmaceuticals usable salts in the control or prevention of diseases, or in the improvement of health, in particular in the control or prevention of high blood pressure and heart failure.
• alkyl used in the present description - alone or in combination - means straight-chain and branched, saturated hydrocarbon radicals having 1-8, preferably 1-4, carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, Isobutyl, sec-butyl, t-butyl, pentyl, hexyl and the like.
• alkoxy means alkyl ether groups, where the term “alkyl” has the same meaning as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t-butoxy and the like.
• cycloalkyl means saturated cyclic hydrocarbon radicals having 3-8, preferably 3-6, carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
• alkanoyl alone or in combination - means the acid residue of a straight-chain or branched alkanoic acid having 1-8, preferably 1-4, carbon atoms, such as formyl, acetyl, propionyl, butyryl, valeryl, isovaleryl and the like.
• heterocycloalkyl similarly relates to saturated, 3-8-membered, preferably 5- or 6-membered, cyclic hydrocarbon radicals, in which one or two methylene groups by one or two oxygen, sulfur or optionally by alkyl, phenylalkyl, Alkylcarbonyl or alkylcarbonyloxy substituted nitrogen atoms are replaced, such as piperidinyl, pyrazinyl, N-benzylpyrazinyl, morpholinyl, N-methylpiperidinyl, N-benzylmorpholinyl and the like.
• cycloalkenyl refers to an unsaturated hydrocarbon radical having 3-8, preferably 3-6, carbon atoms, such as 1-cyclohexenyl, 1,4-cyclohexadienyl and the like.
• heterocycloalkenyl similarly relates to unsaturated, 3-8-membered, preferably 5- or 6-membered, cyclic hydrocarbon radicals, in which one or two methylene groups by one or two oxygen, sulfur or optionally by alkyl, phenylalkyl, Alkylcarbonyl or alkylcarbonyloxy substituted nitrogen atoms, such as dihydropyranyl, Dihydropyridyl, dihydrothienyl and the like.
• aryl denotes an optionally mono- or polysubstituted mono- or bicyclic aromatic hydrocarbon radical having 6-14 carbon atoms, such as phenyl, substituted by alkyl, alkoxy, alkylcarbonyloxy, amino, alkylamino, dialkylamino, alkylcarbonylamino, hydroxy, halogen, trifluoromethyl or nitro, ⁇ - or ⁇ -naphthyl, indenyl, anthryl or phenanthryl and the like.
• heteroaryl denotes an optionally substituted on a nitrogen atom by alkyl, phenyl or phenylalkyl and / or on one or more carbon atoms by alkyl, phenyl, phenylalkyl, halogen, hydroxy, alkoxy, phenyalkoxy or oxo and partially saturated mono- or bicyclic aromatic Hydrocarbon radical in which one or more carbon atoms are replaced by one or two nitrogen atoms and / or an oxygen or sulfur atom, such as pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl , Quinoxalinyl, ⁇ -carbolinyl or a benzene-fused cyclopenta-, cyclohexa-
• arylalkyl denotes straight-chain or branched alkyl groups in which one or more hydrogen atoms have been replaced by aryl groups, such as benzyl, diphenylmethyl, trityl, ⁇ - or ⁇ -naphthylmethyl, 2-phenylethyl, 3-phenyl-2-propyl, 4-phenyl -3-butyl, 2- ( ⁇ - or ⁇ -naphthyl) ethyl, 3- ⁇ -naphthyl-2-propyl, 4- ⁇ -naphthyl-3-butyl and the same, where the aromatic radical can be substituted one or more times as indicated above.
• substituted phenyl optionally denotes mono- or polysubstituted phenyl, such as 4-hydroxyphenyl, 4-methoxyphenyl, 4-methylphenyl, 4-chlorophenyl and the like, by alkyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, hydroxy, halogen or trifluoromethyl.
• substituted amino means a mono- or di-substituted by alkyl, arylalkyl, alkylcarbonyl, alkoxycarbonyl or arylalkoxycarbonyl, or a nitrogen atom optionally substituted by an oxygen, sulfur or optionally alkyl, phenylalkyl, alkylcarbonyl or alkylcarbonyloxy substituted nitrogen atom C3-C6 alkylene disubstituted amino group.
• C3-C6 alkylene denotes straight-chain or branched radicals having 3-6 carbon atoms, such as trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene and the like.
• acyl relates to the acyl group of a carboxylic acid, an optionally N-substituted carbamic acid, a sulfonic acid or an optionally N-substituted amidosulfonic acid, in particular those with the partial formulas Ra-CO-, (Ra) (Ra) N-CO-, Ra -SO2-, or (Ra) (Ra) N-SO2-, wherein Ra is hydrogen, an unsubstituted or substituted, saturated, optionally functionalized with amino, monoalkylamino, dialkylamino, alkanoylamino or alkanoylamino aliphatic, cycloaliphatic, cycloaliphatic-aliphatic to hydrocarbon radical 10, preferably 6, carbon atoms, an unsubstituted or substituted aromatic, heteroaromatic, aromatic-aliphatic or heteroaromatic-aliphatic hydrocarbon radical having up to 18, preferably 10, carbon atoms or an unsubstituted or substituted,
• O-protecting group means a protecting group which can be split off with base or preferably with acid, such as the tetrahydropyranyl or methoxymethyl radical, an alkylcarbonyloxymethyl or alkoxycarbonyl oxymethyl and the like.
• acid such as the tetrahydropyranyl or methoxymethyl radical, an alkylcarbonyloxymethyl or alkoxycarbonyl oxymethyl and the like.
• cyclic O-protecting groups are acetals and ketals, such as the ketal of acetone or the acetal of pivalaldehyde or benzaldehyde.
• Ra is, for example, unsubstituted or substituted or substituted alkyl, mono-, bi- or tricycloalkyl or cycloalkylalkyl.
• "Substituted alkyl” mean an alkyl radical in which one or more hydrogen atoms can be substituted by hydroxyl, alkoxy, alkylcarbonyloxy, halogen, amino or oxo, the substituents only being in the 1-position of the alkyl radical if it is in the partial formula Ra- CO- is present.
• substituted alkyl examples include 2-hydroxyethyl, methoxymethyl, 2-methoxyethyl, acetoxymethyl, 2-acetoxyethyl, chloromethyl, bromomethyl, 2-chloro or 2-bromoethyl, 2-oxopropyl, 2-oxobutyl.
• bicycloalkyl refers to bicyclic saturated hydrocarbon radicals having 5-10, preferably 6-9, carbon atoms, such as bicyclo [3.1.0] hex-1-yl, bicyclo [3.1.0] hex-2-yl, bicyclo [3.1 .0] hex-3-yl, bicyclo [4.1.0] hept-1-yl, bicyclo [4.1.0] hept-4-yl, bicyclo [2.2.1] hept-2-yl, bicylo- [3.2. 1] oct-2-yl, bicyclo [3.3.0] oct-3-yl, bicyclo [3.3.1] non-9-yl, ⁇ - or ⁇ -decahydronaphthyl and the like.
• tricycloalkyl refers to a tricyclic saturated hydrocarbon residue with 8-10 carbon atoms, such as 1-adamantyl.
• cycloalkylalkyl examples include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl and the like.
• cycloaliphatic and cycloaliphatic-aliphatic radicals mentioned can be substituted by the same substituents as alkyl.
• An optionally substituted aromatic or aromatic-aliphatic hydrocarbon radical is, for example, unsubstituted or substituted aryl or arylalkyl.
• the heterocycle is mono-, bi- or tricyclic and contains one to two nitrogen atoms and / or an oxygen or sulfur atom and is with one of its ring carbon atoms with the group -CO-,> N- CO-, -SO2 or> N-SO2- linked.
• heteroaromatic hydrocarbon radicals examples include pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, ⁇ -carbolinyl or a benz-fused cyclopenta-, cyclohexa- or cyclohepta-fused derivative of these Leftovers.
• the heteroaromatic radical can be substituted on a nitrogen atom by alkyl, phenyl or phenylalkyl, for example benzyl, and / or on one or more carbon atoms by alkyl, phenyl, phenylalkyl, halogen, hydroxy, alkoxy, phenylalkoxy or oxo and partially saturated.
• heteroaromatic radicals are 2- or 3-pyrrolyl, phenylpyrrolyl, for example 4- or 5-phenyl-2-pyrrolyl, 2-furyl, 2-thienyl, 2-imidazolyl, 2-, 3- or 4-pyridyl, 2- , 3- or 5-indolyl, substituted 2-indolyl, for example 1-methyl, 5-methyl, 5-methoxy, 5-benzyloxy, 5-chloro or 4,5-dimethyl-2-indolyl, 1-benzyl-2-indolyl, 1-benzyl-3-indolyl, 4,5,6,7-tetrahydro-2-indolyl, cyclohepta [b] -5-pyrrolyl, 2-, 3- or 4-quinolyl, 4 -Hydroxy-2-quinolyl, 1-, 3- or 4-isoquinolyl, 1-oxo-1,2-dihyro-3-isoquinolyl, 2-quinoxalinyl, 2-benz
• heteroaromatic-aliphatic hydrocarbon radicals 2- or 3-pyrrolylmethyl, 2-, 3- or 4-pyridylmethyl, 2- (2-, 3- or 4-pyridyl) ethyl, 4-imidazolylmethyl, 2- (4-imidazolyl) ethyl , 2-indolylmethyl, 3-indolylmethyl, 2- (3-indolyl) ethyl, 2-quinolylmethyl and the like.
• a saturated 5- or 6-membered heterocycle has at least one carbon atom, 1-3 nitrogen atoms and optionally an oxygen or sulfur atom as ring members and is with one of its ring carbon atoms with the group -CO-,> N-CO-, -SO2- or > N-SO2- linked.
• the heterocycle can be on one of its carbon atoms or on a ring nitrogen atom by alkyl, e.g. Methyl or ethyl, phenyl or phenylalkyl, e.g. Benzyl, or substituted on one of its carbon atoms by hydroxy or oxo and / or benzannelated on two adjacent carbon atoms.
• heterocycles examples include pyrrolidin-3-yl, 4-hydroxypyrrolidin-2-yl, 5-oxopyrrolidin-2-yl, piperidin-2-yl, piperidin-3-yl, 1-methylpiperidin-2-yl, 1-methylpiperidine 3-yl, 1-methylpiperidin-4-yl, morpholin-2-yl, morpholin-3-yl, thiomorpholin-2-yl, thiomorpholin-3-yl, 1,4-dimethylpiperazin-2-yl, 2-indolinyl, 3-indolinyl, 1,2,3,4-tetrahydroquinol-2-, -3- or -4-yl, 1,2,3,4-tetrahydroisoquinol-1-, -3- or -4-yl, 1- Oxo-1,2,3,4-tetrahydroisoquinol-3-yl and the like.
• salts includes salts with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like.
• inorganic or organic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like.
• the compounds of formula I have at least three asymmetric carbon atoms and are therefore in the form of optically pure diastereomers, diastereomer mixtures, diastereomeric racemates or mixtures of diastereomeric racemates.
• the present invention encompasses all forms. Diastereomeric mixtures, diastereomeric racemates or mixtures of diastereomeric racemates can be separated by customary methods, e.g. by column chromatography, thin layer chromatography, HPLC and the like.
• Preferred compounds of the formula I are those in which R 1 is hydrogen.
• R2 is preferably imidazol-2-yl, imidazol-4-yl or thiazol-4-yl, particularly preferably imidazol-4-yl.
• Further preferred compounds of the formula I are those in which R3 is cyclohexylmethyl.
• R4 and R5 independently of one another are preferably each hydrogen or alkanoyl which is monosubstituted or substituted by methoxy or together the acetal of pivalaldehyde, particularly preferably each hydrogen.
• R6 denotes group (b).
• A is group (c).
• the preferred meaning of R9 is hydrogen.
• R10 and R11 are each alkyl or, together with the carbon atom to which they are attached, cycloalkyl, particularly preferably methyl, ethyl, cyclopropyl or cyclobutyl.
• R12 is preferably phenyl or substituted phenyl, particularly preferably phenyl.
• the preferred meaning of R13 is alkylcarbonylalkyl or alkylsulfonylalkyl, preferably C1-C4-alkylcarbonylmethyl or C1-C4-alkylsulfonylmethyl.
• Z preferably means the Group Ra-CO-, in which Ra is an optionally substituted, saturated aliphatic hydrocarbon radical having up to 10 carbon atoms or an optionally substituted heteroaromatic hydrocarbon radical having up to 18 carbon atoms, very particularly preferably the group Ra-CO-, in which Ra is a saturated, aliphatic hydrocarbon radical with up to 6 carbon atoms or a heteroaromatic radical with up to 10 carbon atoms.
• R1 is hydrogen
• R2 imidazol-4-yl R3 cyclohexylmethyl
• R4 and R5 are each hydrogen
• R6 is the group (b)
• R9 is hydrogen
• R10 and R11 are each Methyl or ethyl or together with the carbon atom to which they are attached, mean cyclopropyl or cyclobutyl
• R12 phenyl and R13 C1-C4-alkylcarbonylmethyl or C1-C4-alkylsulfonylmethyl R1 is hydrogen
• R2 imidazol-4-yl R3 cyclohexylmethyl
• R4 and R5 are each hydrogen
• R6 is the group (b)
• R9 is hydrogen
• R10 and R11 are each Methyl or ethyl or together with the carbon atom to which they are attached, mean cyclopropyl or cyclobutyl
• Special compounds of formula I are those in which R1 is hydrogen, R2 propyl, imidazol-2-yl, imidazol-4-yl, thiazol-4-yl, thien-2-yl or t-butoxy, R3 cyclohexylmethyl, R4 and R5 independently from each other hydrogen, optionally substituted by dialkylamino, carboxy or alkoxy alkanoyl or together a cyclic O-protecting group, R6 the group (a) or (b), A the group (c) or (d), D a methine group, R7 alkyl , R8 hydrogen or alkyl, or R7 and R8 together with the two atoms connecting them, aryl, heteroaryl or cycloalkenyl, R9 hydrogen or alkyl, R10 and R11 independently of one another each alkyl or the group (s) or together with the carbon atoms, to the they are bound, cycloalkyl or heterocycloalkyl, R12 phen
• Very special compounds of formula I are those in which R1 is hydrogen, R2 imidazol-2-yl, imidazol-4-yl or thiazol-4-yl, particularly preferably imidazol-4-yl, R3 cyclohexylmethyl, R4 and R5 are each independently hydrogen , optionally substituted by methoxy alkanoyl or together the acetal of pivalaldehyde, particularly preferably each hydrogen, R6 the group (b), A the group (c), R9 hydrogen, R10 and R11 independently of each other alkyl or together with the carbon atom that they are bonded, cycloalkyl, particularly preferably methyl, ethyl, cyclopropyl or cyclobutyl, R12 phenyl or substituted phenyl, particularly preferably phenyl, and R13 alkylcarbonylalkyl or alkylsulfonylalkyl, particularly preferably C1-C4-alkylcarbonylmethyl or C1
• Particularly preferred compounds of the formula I are: - (S) -N - [(1S, 2R, 3RS) -1- (cyclohexylmethyl) -4-ethyl-2,3-dihydroxyhexyl] - ⁇ - [(R) - ⁇ - (3,3-dimethyl-2 -oxobutyl) hydrocinnamamido] imidazole-4-propionamide; - (S) -N - [(1S, 2R, 3S) -3-cyclohexyl-1- (cyclohexylmethyl) -2,3-dihydroxypropyl] - ⁇ - [(R) - ⁇ - (3,3-dimethyl-2 -oxobutyl) hydrocinnamamido] imidazole-4-propionamide; - (S) -N - [(1S, 2R, 3S) -1- (cyclohexylmethyl) -2,3-dihydroxy-4-
• Still further particularly preferred compounds of the formula I are: - (S) -N - [(1S, 2R, 3S) -1- (cyclohexylmethyl) -3-cyclopropyl-2,3-dihydroxypropyl] - ⁇ - [(S) - ⁇ - [(morpholinocarbonyl) methyl] hydrocinnamamido] imidazole-4-propionamide; - (S) - ⁇ - [(S) - ⁇ - [(t-butylsulfonyl) methyl] -1-naphthalene propionamido] -N - [(1S, 2R, 3S) -1- (cyclohexylmethyl) -3-cyclopropyl-2 , 3-dihydroxypropyl] imidazole-4-propionamide; - (S) - ⁇ - [(S) -2 - [(t-butylsulfonyl) methyl] -4-pheny
• Very particularly preferred compounds of the formula I are: - (S) -N - [(1S, 2R, 3S) -1- (cyclohexylmethyl) -3-cyclopropyl-2,3-dihydroxypropyl] - ⁇ - [(R) - ⁇ - (3,3-dimethyl-2 -oxobutyl) hydrocinnamamido] imidazole-4-propionamide; - (S) - ⁇ - [(S) - ⁇ - [(t-butylsulfonyl) methyl] hydrocinnamamido] -N - [(1S, 2R, 3S) -1- (cyclohexylmethyl) -3-cyclopropyl-2,3- dihydroxypropyl] imidazole-4-propionamide; - (S) - ⁇ - [(S) - ⁇ - [(t-butylsulfonyl) methyl] hydrocinnamamido]
• acylation of a compound of formula II is carried out according to methods known per se.
• Suitable acylating agents are in particular activated acid derivatives such as esters, mixed esters, acid halides and acid anhydrides or mixed acid anhydrides.
• the reaction is carried out in an organic solvent or solvent mixture which is inert under the reaction conditions at a temperature between about 0 ° C. and room temperature.
• Aromatic hydrocarbons such as benzene, toluene or xylene, chlorinated hydrocarbons such as methylene chloride or chloroform, ethers such as diethyl ether, tetrahydrofuran or dioxane, and the like are particularly suitable as solvents.
• the reaction takes place under reaction conditions customary in peptide chemistry, i.e. preferably in the presence of a condensing agent such as HBTU (O-benzotriazolyl-N, N, N ', N'-tetramethyluronium hexafluorophosphate), BOP (benzotriazol-1-yloxy-bis- (dimethylamino) phosphonium hexafluorophosphate), HOBT (N-hydroxybenzotriazole ), DBU (1,8-diazabicyclo [5.4.0] undec-7-ene), DCC (dicyclohexylcarbodiimide), EDC (N-ethyl-N ′ (3-dimethylaminopropyl) carbodiimide hydrochloride), Hunig base (ethyldiisopropylamine), and the like.
• HBTU O-benzotriazolyl-N, N, N ', N'-tetramethylur
• the reaction is expediently carried out in an organic solvent or solvent mixture which is inert under the reaction conditions at a temperature between about 0 ° and 50 ° C., preferably at about room temperature.
• organic solvent or solvent mixture which is inert under the reaction conditions at a temperature between about 0 ° and 50 ° C., preferably at about room temperature.
• Particularly suitable solvents are dimethylformamide, methylene chloride, acetonitrile, tetrahydrofuran, and the like.
• reaction of a compound of formula III with a compound of formula IV is also carried out according to methods known per se in peptide chemistry, ie under the same conditions as stated above for the reaction of a compound of formula II with a dipeptide.
• suitable activated derivatives of a compound of formula IV are acid halides, acid anhydrides, acid acidic, mixed anhydrides, esters, mixed esters, and the like.
• the reaction of a compound of formula I, wherein R4 and R5 are each hydrogen, with an alkanoylating agent is also carried out according to methods known per se.
• Suitable alkanoylating agents are alkanoic anhydrides and halides, preferably chlorides.
• the reaction takes place in an organic solvent or solvent mixture which is inert under the reaction conditions at a temperature between about room temperature and the reflux temperature of the reaction mixture, preferably at about room temperature.
• the reaction can be carried out in the presence or absence of an acid binder such as sodium or potassium carbonate, pyridine, triethylamine and the like.
• reaction of a compound of formula I, in which R4 and R5 are each hydrogen, with an agent which forms an O-protecting group also takes place in a manner known per se.
• the tetrahydropyranyl ethers can be prepared by reaction with dihydropyran in the presence of an acid catalyst such as p-toluenesulfonic acid and the like, and the acetone ketal by reaction with 2,2-dimethoxypropane in the presence of an acid catalyst such as p-toluenesulfonic acid.
• the starting materials of formula II are new and also the subject of the present invention. These compounds can be prepared by reacting a compound of formula III with optionally N-methylated histidine, leucine, norleucine, norvaline, thiazolylalanine, thienylalanine or t-butoxyserine. This reaction also takes place according to methods known in peptide chemistry, ie under the reaction conditions as described above for the reaction of a compound of formula II with a dipeptide.
• the starting materials of formula III are also new and the subject of the present invention. They can be prepared, for example, by working in a compound of the general formula wherein B represents an amino protecting group, preferably t-butoxycarbonyl or benzyloxycarbonyl, and R3 and R6 have the meaning given above, cleaves the amino protecting group and optionally also the O protecting group at the same time or by using a compound of the general formula wherein R3 and R6 have the meaning given above, treated with a base.
• the N-protecting group and optionally the O-protecting group are also cleaved by methods known per se, for example in an organic solvent or solvent mixture which is inert under the reaction conditions at a temperature between about 0 ° C. and room temperature with an acid, such as hydrochloric acid, trifluoroacetic acid, and the same.
• Suitable solvents are ethers, such as tetrahydrofuran or dioxane, alcohols, such as methanol, or chlorinated hydrocarbons, such as methylene chloride, and the like.
• a compound of formula VII takes place according to methods known per se in a solvent or solvent mixture which is inert under the reaction conditions at a temperature between about room temperature and the reflux temperature.
• Suitable solvents are, for example, methanol, ethanol, dioxane, tetrahydrofuran, water or mixtures thereof.
• Suitable bases are suitably sodium, potassium or barium hydroxide and the like.
• the starting materials of the formula IV are known or can be obtained analogously to the preparation of the known compounds.
• the compounds of the formulas V and VI are also new and are the subject of the present invention. You can, for example, by reducing the corresponding keto compounds of the general formula wherein B, R3 and R6 have the meaning given above, getting produced.
• a keto compound of the formula VIII or IX likewise takes place according to methods known per se, for example using a complex metal hydride such as sodium borohydride and the like, in an organic solvent or inert under the reaction conditions Solvent mixture at a temperature between about 0 ° C and about room temperature.
• a complex metal hydride such as sodium borohydride and the like
• the compounds of formula VII are also new and the subject of the present invention. You can, for example, by reacting the corresponding formyl compounds of the general formula where R3 has the meaning given above, be produced with an organometallic compound which gives off the rest R6.
• the reaction with an organometallic compound also takes place according to methods known per se, for example in a solvent which is inert under the reaction conditions, such as an ether, at a temperature between about -100.degree. C. and 50.degree. If a lithium compound is used, the reaction is preferably carried out at about -50 ° C to about -80 ° C, while when using a Grignard compound the reaction is preferably carried out at about room temperature.
• the compounds of formulas VIII, IX and X are also new and the subject of the present invention.
• the compounds of formula VIII can be prepared, for example, by using an ester or a cyanohydrin of the general formula in which B and R3 are as defined above, R15 is alkyl and R16 is preferably trimethylsilyl, with a compound of the general formula W-Mg-R6 XIII wherein R6 has the meaning given above and W is chlorine, bromine or iodine, preferably bromine, implemented in a Grignard reaction.
• This reaction is also carried out according to methods known per se, for example in a solvent which is inert under the reaction conditions, such as an ether, at a temperature between about 0 ° C.
• the intermediate imine must be hydrolyzed with a weak aqueous acid, such as phosphoric acid, the trimethylsilyl group being split off at the same time.
• the compounds of formula IX can be prepared, for example, by using an ester of the general formula wherein B, R3 and R15 have the meaning given above, with a lithium compound of the general formula R6-Li XV where R6 has the meaning given above, implements.
• This reaction also takes place according to methods known per se, for example in a solvent which is inert under the reaction conditions, such as an ether, at a temperature between about -100.degree. C. and 0.degree. C., preferably at about -70.degree.
• the compounds of formula X are also new and the subject of the present invention. They can be prepared, for example, by using a compound of the general formula where R3 has the meaning given above, undergoes reductive ozonolysis.
• the reaction with ozone is also carried out according to methods known per se, for example in methanol or methylene chloride as solvent at a temperature between about -100 ° C and -20 ° C.
• the subsequent reduction of the ozonides is also carried out according to methods known per se, for example by adding dimethyl sulfide at a temperature between about -50 ° C. and room temperature.
• Another process for the preparation of the compounds of formula V is that a compound of general formula wherein B, R3 and R6 have the meaning given above, oxidized.
• the oxidation of a compound of formula XVII also takes place according to methods known per se in an organic solvent or solvent mixture which is inert under the reaction conditions at a temperature between about room temperature and the boiling point of the solvent or solvent mixture, preferably at about room temperature.
• Osmium tetroxide is particularly suitable as an oxidizing agent.
• Pyridine and the like are particularly suitable as solvents.
• the compounds of formula XVII are also new and the subject of the present invention. They can be prepared by methods known per se, for example by reacting an aldehyde of the general formula wherein B and R3 have the meaning given above, with an appropriate Wittig reagent. The reaction is also carried out by known methods, for example in a solvent which is inert under the reaction conditions, such as an ether, in a Temperature between about -50 ° C and room temperature.
• a compound of formula VI can also be prepared by adding a compound of general formula wherein B and R3 have the meaning given above, in a Grignard reaction with a compound of the formula XIII, ie under the same conditions as above for the reaction of a compound of the formula XI with a compound of the formula XIII.
• the compounds of the formula XIX are known or can be prepared analogously to the known compounds.
• the compounds of formula I and their pharmaceutically usable salts have an inhibitory effect on the natural enzyme renin.
• the latter enters the blood from the kidneys and there causes the cleavage of angiotensinogen to form the decapeptide angiotensin I, which is then broken down in the lungs, kidneys and other organs to form the octapeptide angiotensin II.
• Angiotensin II increases blood pressure both directly through arterial constriction and indirectly through the release of the sodium ion-retaining hormone aldosterone from the adrenal glands, which is associated with an increase in the extracellular fluid volume.
• the test is carried out in Eppendorf tubes.
• the incubation mixture consists of (1) 100 ul human renin in buffer A (0.1M sodium phosphate solution, pH 7.4, containing 0.1% bovine serum albumin, 0.1% sodium azide and 1mM ethylenediaminetetraacetic acid), sufficient for renin activity from 2-3 ng angiotensin I / ml / hour; (2) 145 ⁇ l buffer A; (3) 30 ⁇ l of 10 ⁇ M human tetradecapeptide renin substrate (hTD) in 10 mM hydrochloric acid; (4) 15 ⁇ l of dimethyl sulfoxide with or without inhibitor and (5) 10 ⁇ l of a 0.03 molar solution of hydroxyquinoline sulfate in water.
• buffer A 0.1M sodium phosphate solution, pH 7.4, containing 0.1% bovine serum albumin, 0.1% sodium azide and 1mM ethylenediaminetetraacetic acid
• hTD human tetradecapeptide ren
• angiotensin I 100%; Angiotensin II 0.0013%; hTD (angiotensin I-Val-Ile-His-Ser-OH) 0.09%.
• the production of angiotensin I is determined by the difference between the test at 37 ° C and that at 4 ° C.
• IC50 values which denote the concentration of the inhibitor at which the enzymatic activity is inhibited by 50%.
• the IC50 values are determined from a linear regression curve from a logit-log plot.
• G (S) - ⁇ - [(S) - ⁇ - [(t-butylsulfonyl) methyl] hydrocinnamamido] -N - [(1S, 2R, 3S) -1- (cyclohexylmethyl) -2,3-dihydroxy-4 -methylpentyl] imidazole-4-propionamide;
• H (S) - ⁇ - [(S) - ⁇ - [(t-butylsulfonyl) methyl] hydrocinnamamido] -N - [(1S, 2R, 3S) -3-cyclohexyl-1- (cyclohexylmethyl) -2.3 -dihydroxypropyl] imidazole-4-propionamide.
• the compounds of formula I and their pharmaceutically usable salts can be used as medicaments, e.g. in the form of pharmaceutical preparations.
• the pharmaceutical preparations can be administered enterally, such as orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions, nasally, e.g. in the form of nasal sprays, or rectally, e.g. in the form of suppositories.
• administration can also be parenteral, such as intramuscularly or intravenously, e.g. in the form of injection solutions.
• the compounds of the formula I and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic excipients.
• excipients one can e.g. for tablets, coated tablets and hard gelatin capsules, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc.
• Suitable excipients for soft gelatin capsules are e.g. vegatable oils, waxes, fats, semi-solid and liquid polyols etc.
• Suitable excipients for the production of solutions and syrups are e.g. Water, polyols, sucrose, invert sugar, glucose etc.
• Suitable excipients for injection solutions are e.g. Water, alcohols, polyols, glycerin, vegetable oils etc.
• excipients are e.g. natural or hardened oils, waxes, fats, semi-liquid or liquid polyols etc.
• the pharmaceutical preparations can also preservatives, solubilizers, increase viscosity de Contain substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for changing the osmotic pressure, buffers, coating agents or antioxidants. They can also contain other therapeutically valuable substances.
• the compounds of the general formula I and their pharmaceutically usable salts can be used in the control or prevention of high blood pressure and heart failure.
• the dosage can vary within wide limits and is of course to be adapted to the individual circumstances in each individual case.
• a daily dose of about 3 mg to about 3 g, preferably about 10 mg to about 1 g, e.g. about 300 mg per person, preferably in 1-3 single doses, e.g. can be the same size, be appropriate, but the upper limit just specified can also be exceeded if this should prove to be appropriate.
• Children are usually given half the dose of adults.
• the reaction mixture is then evaporated to dryness in a high vacuum, the residue is poured onto a mixture of ice and 2N sodium bicarbonate solution and extracted three times with ethyl acetate. The extracts are washed successively with saturated ammonium chloride solution, 2N sodium bicarbonate solution and saturated sodium chloride solution and combined. After drying the organic solution over magnesium sulfate, the solvent is evaporated under reduced pressure and the residue (1.01 g) is purified on 70 g of silica gel using a 20: 1: 0.1 mixture of methylene chloride, methanol and ammonia Chromatograph eluent.
• the residue is concentrated in a mixture of 200 ml of glacial acetic acid and 200 ml. Hydrochloric acid dissolved, and the reaction mixture heated to reflux overnight. The reaction mixture is then reduced Evaporated pressure, and the residue partitioned between 800 ml of water and 800 ml of ether. The organic phase is washed twice with 400 ml of water and the wash water is combined with the aqueous phase. Then the water is evaporated, and the residue is mixed twice in succession, first with toluene and then evaporated to dryness again.
• reaction mixture is then poured onto 100 ml of an ice-cold saturated ammonium chloride solution, the organic phase is separated off and the aqueous phase is extracted twice with 300 ml of ether each time.
• the two ether extracts are washed with 100 ml of saturated ammonium chloride solution, combined and dried over magnesium sulfate.
• the three ethyl acetate extracts are washed successively with 70 ml of saturated ammonium chloride solution, 70 ml of 2N sodium bicarbonate solution and 70 ml of saturated sodium chloride solution, combined, dried over magnesium sulfate, filtered and evaporated.
• the crude product obtained (2.2 g) is stirred in 60 ml of methylene chloride and 2 ml of piperidine for 3 hours at room temperature. The reaction mixture is then evaporated and the residue is triturated from 50 ml of hexane and filtered off.
• the propionamides used as starting materials were produced as follows:
• This compound was, likewise in an analogous manner as described in Example 1, by reacting t-butyl [(1S, 2R) -1- (cyclohexylmethyl) -2-hydroxy -3- (methoxycarbonyl) ethyl] carbamate with isopropyl magnesium bromide, reduction of t-butyl [(1S, 2R) -1- (cyclohexylmethyl) -2-hydroxy-4-methyl -3-oxopentyl] carbamate obtained with sodium borohydride, chromatographic separation of the isomers obtained, elimination of the Boc protective group from t-butyl [( 1S, 2R, 3S) -1- (cyclohexylmethyl) -2,3-dihydroxy -4-methylpentyl] carbamate with hydrochloric acid in dioxane, reaction with (Fmoc) 2His-OH and elimination of the two protective groups with piperidine.
• the propionamides used as starting materials were produced as follows:
• Boc protective group is split off from the two epimeric carboxylates with methanolic hydrochloric acid, the crude products obtained are coupled with (Fmoc) 2His-OH and finally the two protective groups are removed with piperidine.
• the propionamides used as starting materials were produced as follows:
• reaction mixture is stirred for 1 hour at room temperature, then cooled to -70 ° and a solution of 23 g (90 mmol) of t-butoxycarbonylamino- (3S) -cyclohexylpropylaldehyde is added dropwise within 45 minutes. Then the reaction mixture is allowed to slowly warm to room temperature overnight. Then first 10 ml of methanol and then 500 ml of saturated sodium potassium tartrate solution are added. The reaction mixture was poured onto ice and extracted three times with ethyl acetate. The organic phases are washed with water and 2N sodium bicarbonate solution, dried and evaporated.
• This compound was prepared in a manner analogous to that described in Example 1 by splitting off the Boc protective group with hydrochloric acid in dioxane, reacting with (Fmoc) 2His-OH, splitting off the two protective groups with piperidine and chromatographically separating the two isomers into (S) - ⁇ - Amino-N - [(1S, 2R, 3S) -1- (cyclohexylmethyl) -2,3-dihydroxy-4-methylpentyl] imidazole-4-propionamide and (S) - ⁇ -amino-N - [(1R, 2S , 3R) -1- (cyclohexylmethyl) -2,3-dihydroxy-4-methylpentyl] imidazole-4-propionamide.
• propionamides were prepared in an analogous manner to that described above: - (S) - ⁇ -Amino-N - [(1S, 2R, 3S) -3-cyclohexyl-1- (cyclohexylmethyl) -2,3-dihydroxypropyl] imidazole-4-propionamide and the diastereomeric (S) - ⁇ - Amino-N - [(1R, 2S, 3R) -3-cyclohexyl-1- (cyclohexylmethyl) -2,3-dihydroxypropyl] imidazole-4-propionamide using cyclohexylmethyl bromide instead of isobutyl bromide to prepare the Wittig reagent; - (S) - ⁇ -Amino-N - [(1S, 2R, 3S) -1- (cyclohexylmethyl) -3-cyclopropyl-2,3-dihydroxypropyl] imidazole-4-pro
• reaction mixture is then evaporated under reduced pressure and the crude (RS) - ⁇ - [(t-butylthio) methyl] -p-methoxyhydrocinnamic acid obtained is then suspended in 200 ml of methylene chloride. 5.66 g (32.8 mmol) of 3-chloroperbenzoic acid are added in portions to the suspension while cooling with ice, and the mixture is then stirred at room temperature overnight. Then the reaction mixture is washed successively with 10% potassium iodide solution and water, dried over sodium sulfate and evaporated under reduced pressure. The residue is triturated with ether, the solid is filtered off and the ethereal phase is evaporated under reduced pressure.
• reaction mixture is then allowed to warm to room temperature and extracted with ether.
• the ether phase is washed successively with water and sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure.
• the oily residue (1 g) is reacted with ethereal diazomethane solution. After evaporation of the reaction solution, the two diastereo are cleaned and separated mere ester by chromatography on silica gel using a 4: 1 mixture of hexane and ether.
• reaction mixture is concentrated to about 1/4 of the original volume under reduced pressure, then diluted with 50 ml of ethyl acetate and washed successively with water, saturated sodium bicarbonate solution, water and saturated sodium chloride solution.
• the organic phase is dried over sodium sulfate and evaporated under reduced pressure, and the residue is chromatographed on silica gel using a 98: 2 mixture of methylene chloride and methanol as the eluent, 140 mg (0.17 mmol) (S) - ⁇ - [( S) - ⁇ - [(t-Butylsulfonyl) methyl] hydrocinnamido] -N - [(1S, 2R, 3S or R) -1- (cyclohexylmethyl) -3- (1-cyclohexen-1-yl) -2.3 -dihydroxypropyl] -1- (2,4-dinitrophenyl) imidazole-4-propionamide can be obtained in
• reaction mixture is then left to stand in the refrigerator overnight, then stirred for another 30 minutes and evaporated to dryness.
• the residue is extracted three times with 600 ml of ether each time, and the organic phase is washed twice with 300 ml of water each time, dried over magnesium sulfate, filtered and evaporated to give 54.5 g of a foam.
• This foam is dissolved in 150 ml of methanol and mixed with 31.51 g (228 mmol) of potassium carbonate and stirred for 3 hours at room temperature under argon.
• N - [(S) - ⁇ - [(t-butylsulfonyl) methyl] hydrocinnamoyl] -3- (2,4-dinitrophenyl) -L-histidine used as starting material was prepared as follows: 15.8 g (65.5 mmol) of L-histidine methyl ester dihydrochloride, 18.6 g (S) - ⁇ - [(t-butylsulfonyl) methyl] hydrocinnamic acid, 28.9 g BOP and 35.8 ml Hünig base are added in 400 ml of acrylonitrile dissolved and then stirred for 12 hours at room temperature.
• the amines used as starting materials were produced as follows:
• reaction mixture is hydrolyzed with 100 ml of ice-cold, saturated ammonium chloride solution, and the organic phase is separated off.
• the aqueous phase is extracted twice with 300 ml of ether each time.
• the combined organic phases are dried over sodium sulfate and evaporated under reduced pressure.
• the residue is chromatographed on silica gel using a 3: 1 mixture of toluene and ethyl acetate as the eluent.
• reaction solution is concentrated to about 1/3 of its volume under reduced pressure and then diluted with 200 ml of ethyl acetate. After adding 50 ml of ice water, the reaction mixture is adjusted to pH 2.5 and the aqueous phase is saturated with solid sodium chloride. The aqueous phase is extracted twice more with ethyl acetate, and the combined ethyl acetate phases are dried over sodium sulfate and evaporated.
• the protected propionamide used as the starting material was produced as follows:
• This compound could be refluxed in diethylamine for 90 minutes in (1S, 2R) -2 - [(S) -1 - [(S) - ⁇ - [(S) - ⁇ - [(t-butylsulfonyl) methyl ] hydrocinnamamido] imidazole-4-propionamido] -2-cyclohexylethyl] -1-cyclopropylethylene-bis (diethylaminoacetate), MS 857 (M + H) +.
• a sterile filtered aqueous solution of (S) - ⁇ - [(S) - ⁇ - [(t-butylsulfonyl) methyl] hydrocinnamamido] -N - [(1S, 2R, 3S) -1- (cyclohexylmethyl) -2,3- dihydroxy -4-methylpentyl] imidazole-4-propionamide is mixed while heating with a sterile gelatin solution containing phenol as a preservative under aseptic conditions so that 1.0 ml solution has the following composition: (S) - ⁇ - [(S) - ⁇ - [(t-butylsulfonyl) methyl] hydrocinnamamido] -N - [(1S, 2R, 3S) -1- (cyclohexylmethyl) -2,3-dihydroxy-4-methylpentyl ] imidazole-4-propionamide 3.0 mg gelatin 150.0 mg phenol
• the mixture is filled into vials of 1.0 ml under aseptic conditions.
• galenical preparations can be prepared from the following, likewise preferred compounds: (S) -N - [(1S, 2R, 3S) -1- (cyclohexylmethyl) -3-cyclopropyl-2,3-dihydroxypropyl] - ⁇ - [(R) - ⁇ - (3,3-dimethyl-2- oxobutyl) hydrocinnamamido] imidazole-4-propionamide; (S) - ⁇ - [(S) - ⁇ - [(t-butylsulfonyl) methyl] hydrocinnamamido] -N - [(1S, 2R, 3S) -1- (cyclohexylmethyl) -3-cyclopropyl-2,3-dihydroxypropyl ] imidazole-4-propionamide; (S) - ⁇ - [(S) - ⁇ - [(t-butylsulfonyl

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